The cytokine tumour necrosis factor- (TNF-) is involved (mostly through the activation of inducible nitric oxide synthase) in the pathogenesis of circulatory shock. On the other hand, melanocortin peptides are potent and effective in reversing haemorrhagic shock, both in animals (rat, dog) and in humans. This prompted us to study the influence of the melanocortin peptide ACTH-(1–24) on the blood levels of TNF- in haemorrhage-shocked rats and on the in vitro production of TNF- by lipopolysaccharide (LPS)-activated macrophages. Plasma levels of TNF- were undetectable before starting bleeding and greatly increased 20 min after bleeding termination in saline-treated rats. In rats treated with ACTH-(1–24) the almost complete restoration of cardiovascular function was associated with markedly reduced levels of TNF- 20 min after bleeding termination. On the other hand, ACTH-(1–24) did not influence TNF- plasma levels in sham-operated, unbled rats. In vitro, ACTH-(1–24) (25–100 nM) dose-dependently reduced the LPS-stimulated production of TNF- by peritoneal macrophages harvested from untreated, unbled rats. These results indicate that inhibition of TNF- overproduction may be an important component of the mechanism of action of melanocortins in reversing haemorrhagic shock.